DESCRIPTION: It is proposed to continue investigations in the area of acyclic diastereoselective synthesis, with emphasis on crotylmetalation reactions and fragment assembly aldol reactions in the context of natural products synthesis. Specific goals are: 1. Development of New Methodology for the Synthesis of Anti, Anti Dipropionates. The reactions of b-hydroxy aldehydes with (Z)-crotyltrifluorosilane 36 and (Z)-crotylsilacyclobutanes 112-114 will be developed for the synthesis of anti, anti dipropionates, which are difficult to synthesize by other methods. 2. Stereochemical Studies of Methyl Ketone Aldol Reactions. (i) The involvement of boat-like transition states in methyl ketone aldol reactions will be probed by using the 2H-labeled enol silane 122 as precursor to lithium, boron and titanium enolates. (ii) A synthesis of the C(13)-C(25) segment of scytophycin C will be performed with emphasis on the aldol reaction of 125 and 126. The data that emerge from this study will complement results obtained in the rutamycin series, and should greatly increase the ability to make stereochemical predictions about other complex fragment couplings. 3. New Methodology for Fragment Coupling. Tartrate prenylboronates 136e,z will be developed for use in aldehyde allylboration reactions. The resulting adducts 137 will be elaborated to chiral methallylboronates 138 and then coupled with chiral aldehydes. It is expected that the diastereofacial selectivity of 138 will be large enough to dominate the diastereofacial preferences of most aldehydes. This methodology thus should constitute a general strategy for fragment coupling. 4. Completion of a Total Synthesis of Damavaricin D. This total synthesis, which is at an advanced stage, will be completed in the next grant period. A biomimetic strategy for the synthesis of streptovaricin C from damavaricin C (naturally derived) also will be explored. 5. Completion of a Total Synthesis of Bafilomycin A1. The synthesis, which has progressed to the stage of the macrocycle 85, will be completed by a late stage aldol reaction of methyl ketone 158 and chiral aldehyde 159. 6. Synthesis of Tedanolide. This project will give additional insight into the fragment assembly aldol problem. The crotylboration of meso dialdehyde 190 and the regioselective introduction of trisubstituted olefins via E2 reactions in conformationally flexible systems also will be explored.